法尼基转移酶抑制剂靶向治疗髓系白血病的作用及机制研究
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摘要
目的研究髓系白血病胞外信号调节激酶(ERK)/丝裂原活化蛋白激酶(MAPK)的表达水平及其意义。方法以髓系白血病细胞株HL-60、K562细胞,31例初治急性髓系白血病(AML)、21例初治慢性髓系白血病(CML)和14例AML完全缓解(CR)骨髓细胞为研究对象,应用流式细胞术和Western blot检测磷酸化ERK1/2 (磷酸化P44/42MAPK)和ERK2 (P42MAPK)信号分子的表达。结果流式细胞术检测显示,HL-60、K562细胞,初治AML、初治CML、AML-CR及正常骨髓细胞均表达磷酸化ERK1/2,但表达水平不同;正常细胞表达较低,与AML-CR细胞相比,差异无显著性(P>0.05);HL-60、初治AML细胞与AML-CR、正常细胞相比,以及K562、初治CML细胞与正常细胞相比,磷酸化ERK1/2表达水平均显著增高(P<0.05);其中,高表达磷酸化ERK1/2的初治AML和初治CML比例分别为80.6% (25/31)、61.9% (13/21)。Western blot结果也表明,正常细胞与AML-CR细胞相比,磷酸化ERK1/2(磷酸化P44/42MAPK)和ERK2 (P42MAPK)灰度比值差异无显著性(P>0.05);HL-60、初治AML细胞与正常、AML-CR细胞相比,以及K562、初治CML细胞与正常细胞相比,磷酸化ERK1/2(磷酸化P44/42MAPK)和ERK2 (P42MAPK)灰度比值显著增高(P<0.05);其中,高表达磷酸化ERK1/2 (磷酸化P44/42MAPK)、ERK2(P42MAPK)的初治AML和初治CML比例分别为77.4% (24/31)、52.4%(11/21),与流式细胞术检测结果基本一致。结论构成性激活的ERK/MAPK信号转导途径存在于大多数髓系白血病患者及HL-60、K562细胞株,在介导髓系白血病细胞增殖、存活、凋亡受抑中发挥重要作用,是髓系白血病合理的治疗靶点。
Objective To investigate the expression and pathophysiological significance of extracellular signal-regulated kinase (ERK) / mitogen- activated protein kinase (MAPK) in myeloid leukemia. Methods Myeloid leukemia cell lines HL-60, K562 cells, bone marrow mononuclear cells (BMMNCs) from 31 acute myeloid leukemia (AML)patients at diagnosis, 21 chronic myeloid leukemia (CML) patients at diagnosis and 14 AML patients in complete remission (CR) were examined. The expression levels of phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) were detected by flow cytometry and Western blot. Results There were no difference in the expression levels of phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) between normal BMMNCs and AML-CR BMMNCs. The expression levels of phospho-ERK1/2(phospho-P44/42MAPK) and ERK2 (P42MAPK) in HL-60 cells and BMMNCs from AML patients at diagnosis were significantly higher than those in BMMNCs from AML-CR and normal donors (P<0.05). The expression levels of phospho-ERK1/2 and ERK2 in K562 cells and BMMNCs from CML patients at diagnosis were also significantly higher than those in normal cells(P<0.05). Flow cytometry showed that ratios of phospho-ERK1/2 hyperexpression in AML and CML patients at diagnosis were 80.6%(25/31) and 61.9% (13/21) respectively. Western blot also indicated that ratios of both phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) hyperexpression in AML and CML patients at diagnosis were 77.4%(24/31) and 52.4%(11/21) respectively. Conclusion Constitutive ERK/MAPK phosphorylation was observed in most patients with myeloid leukemia. Constitutive activation of ERK/MAPK signaling pathway plays an important role in the pathogenesis of myeloid leukemia.
Objective To investigate the expression and pathophysiological significance of extracellular signal-regulated kinase (ERK) / mitogen- activated protein kinase (MAPK) in myeloid leukemia. Methods Myeloid leukemia cell lines HL-60, K562 cells, bone marrow mononuclear cells (BMMNCs) from 31 acute myeloid leukemia (AML)patients at diagnosis, 21 chronic myeloid leukemia (CML) patients at diagnosis and 14 AML patients in complete remission (CR) were examined. The expression levels of phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) were detected by flow cytometry and Western blot. Results There were no difference in the expression levels of phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) between normal BMMNCs and AML-CR BMMNCs. The expression levels of phospho-ERK1/2(phospho-P44/42MAPK) and ERK2 (P42MAPK) in HL-60 cells and BMMNCs from AML patients at diagnosis were significantly higher than those in BMMNCs from AML-CR and normal donors (P<0.05). The expression levels of phospho-ERK1/2 and ERK2 in K562 cells and BMMNCs from CML patients at diagnosis were also significantly higher than those in normal cells(P<0.05). Flow cytometry showed that ratios of phospho-ERK1/2 hyperexpression in AML and CML patients at diagnosis were 80.6%(25/31) and 61.9% (13/21) respectively. Western blot also indicated that ratios of both phospho-ERK1/2 (phospho-P44/42MAPK) and ERK2 (P42MAPK) hyperexpression in AML and CML patients at diagnosis were 77.4%(24/31) and 52.4%(11/21) respectively. Conclusion Constitutive ERK/MAPK phosphorylation was observed in most patients with myeloid leukemia. Constitutive activation of ERK/MAPK signaling pathway plays an important role in the pathogenesis of myeloid leukemia.
引文
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